The present invention relates to a series of new carbapenem derivatives which have excellent antibiotic activity and outstanding stability in vivo. By virtue of their enhanced resistance to inactivation by dehydropeptidase I, the compounds of the present invention have improved value in the therapy and prophylaxis of infectious diseases. The invention also provides methods and compositions using these derivatives for the treatment and prophylaxis of infections, as well as processes for their preparation.
The carbapenem compounds are a well known series of compounds, related to the penicillins, which have been used or have been proposed for use as antibiotics. They have in common a basic structure which may be represented by the formula (A): ##STR3##
In this formula, we have indicated the numbering of those positions of importance to the carbapenem compounds, using the numbering scheme commonly used in the art and as employed in the nomenclature of the compounds of the present invention. In accordance with the recommendations of the International Union of Pure and Applied Chemistry (IUPAC), Commision on Nomenclature of Organic Chemistry, the compounds referred to herein are named semi-systematically, using the above carbapenem structure as the parent name.
Those carbapenem antibiotics having no substituent at the 1-position are potentially a very useful series of compounds which have extraordinarily potent antibacterial activity. Unfortunately, however, they are chemically unstable and, moreover, are sensitive to dehydropeptidase I in vivo. Dehydropeptidase I is an enzyme which hydrolyses the .beta.-lactam ring in carbapenem antibiotics and which exists in mammalian tissue, for example in the renal cortex. It is responsible for the extensive metabolisation of many otherwise valuable .beta.-lactam antibiotics in animals, including humans, thus greatly reducing their value. Despite these disadvantages, these carbapenem antibiotics are finding increasing use in the treatment of bacterial infections. A typical and common antibiotic of this type is thienamycin, which has the formula (B): ##STR4##
Metabolism of the antibiotic in vivo may be demonstrated by a low recovery of the compound itself (as opposed to its metabolic products) in the urine, and this has been demonstrated for thienamycin H. Kropp et al., Antimicrob. Agents, Chemother., 22, 62 (1982); and S. R. Norrby et al., ibid., 23, 300 (1983)!.
Although it has been found that carbapenem compounds having a substituent at the 1-position (commonly a 1-methyl group) do not have this susceptibility to dehydropeptidase I in vivo, many of the compounds of this type discovered to date lack sufficient activity. It is, therefore, considered highly desirable to find a carbapenem antibiotic which combines the good activity of thienamycin with a resistance to dehydropeptidase I in vivo.
Many carbapenem compounds are now known. Some are described, for example, in European Patent Publications No. 126 587, 182 213, 333 175, 442 497, 443 883 and 508 602. EP 182 213 and EP 333 175 disclose compounds in which a thio-pyrrolidinyl group and its ring carbon atom substituent are linked by an alkylene group, and thus differ from the compound of the present invention in that there is no linking carbonyl group. The compounds disclosed in EP 126 587, on the other hand, are carboxylic thio-pyrrolidinyl beta-lactam compounds. EP 126 587 and EP 508 682 are thought to represent the closest prior art to the compounds of the present invention. However, the present compounds have demonstrated significantly better activity than the prior art compounds.